Despite a number of newly approved drugs, cancer is responsible for over 20% of all deaths and will soon overtake heart disease as the main killer in the Western world. First generation adenovirus vectors have shown promise in the treatment of locally advanced cancer via intratumoral administration. However, these first generation vectors are not likely to be suitable for treating large-market, metastatic cancers due to their limited efficiency and specificity. Therefore, the development of targeted adenovirus vectors that can efficiently and specifically deliver potent anti-cancer genes to disseminated tumors would be a major advance in the treatment of cancer. The preliminary data in this grant detail an adenovirus vector that is ablated for binding to its native receptors and redirected for binding to the highly tumor-selective receptor, alpha-v-beta-6. Compared to an untargeted vector, it is demonstrated that this vector significantly improved the specificity of gene transfer to a subcutaneous alpha-v-beta-6-expressing lung carcinoma. While the specificity of tumor gene transfer is dramatically improved, the data suggests that the specificity achieved by the vector may require further enhancement. Previous work has shown that modifications that ablate the binding of adenovirus to its native receptors, as highlighted above, are critical for improving specificity. However, recently published research has shown that additional modifications to the adenovirus vector that reduce the length and/or alter the composition of its elongated coat protein, fiber, also significantly reduce gene transfer to non-target organs and thereby improve specificity. The primary objective of this phase I SBIR is to further improve the specificity of the current tumor targeted vector through reducing the length of its fiber coat protein. The long-term objective of this application is to create a breakthrough cancer therapeutic for clinical development based upon an adenovirus vector that efficiently and specifically targets potent antitumor genes to metastatic tumors.